Embracing Novel Frontiers: Tachyon Ventures' First Investment in Palm Therapeutics

The role of proto-oncogenes in cancer

Cancer accounts for about one fifth of all deaths in the United States. Nevertheless, survival rates have improved markedly in recent years, thanks to risk factor reduction (e.g., cutting smoking), early detection (e.g., regular mammograms for women), and improvements in clinical therapies such as surgery, irradiation and pharmaceutical treatments. Unfortunately, the treatment options and survival rates for certain types of cancer remain dismal. Leukemia’s five-year survival is about 50% while liver, brain and pancreatic cancers each have a five-year survival rate < 15%.

Many cancers of different types are caused or exacerbated by mutations in a class of gene called a “proto-oncogene.” This class of gene plays important roles in human development and in the maintenance of tissues and organs. When a proto-oncogene acquires a certain type of damaging mutation, it becomes an “oncogene”: a supercharged version of its former self. Oncogenes contribute to increased cell division, decreased differentiation of cells into cell subtypes, and prevention of natural cell death - all of which are hallmarks of cancer.

The proto-oncogene NRAS, for example, is mutated into oncogenic NRAS in 8% of all cancers, contributing to 1.5M new cancer diagnoses per year. This makes the protein encoded by NRAS a very high value target for pharmaceutical development. Unfortunately, oncogenic (cancer-causing) NRAS, like oncogenic forms of other proteins in the same “RAS family” of proteins, has proven to be very challenging to target due to its lack of suitable protein pockets for small molecules to bind to. Even if an oncogene’s protein product can be successfully targeted by a drug, the drug’s specific mechanism of action may be such that the oncogene can easily develop a new mutation that renders the drug ineffective.

Uncovering the science of palmitoylation

In our search for companies that are developing transformative platforms across multiple cancers and other diseases, we recently came across Palm Therapeutics, a UC San Diego spin-out co-founded by former UC San Diego postdoc Andrew Rudd, PhD, and Professor Neal Devaraj, Ph.D., the Murray Goodman Endowed Chair in Chemistry & Biology at UC San Diego, and a world-renowned expert in lipid chemical biology.

Palm Therapeutics is exploring a new mechanism called palmitoylation as a method of deactivating harmful proteins. Palmitoylation is a particular kind of molecular modification of a residue (or amino acid) of a protein that affects the protein’s function.  In the case of oncogenic NRAS, palmitoylation of residue 181 has recently been shown to be essential for its cancer-causing function. In experimental models of oncogenic NRAS in blood cancer, it has been shown that suppression of palmitoylation completely halts the formation of abnormal cells. Importantly, evidence from genetic studies shows it is very challenging for cells to develop new mutations to circumvent suppression of oncogenic NRAS palmitoylation.

Palmitoylation is a biochemical process that involves adding a type of fatty acid, a palmitate, to a protein. This process is interesting for several reasons. To start, unlike some other types of lipidation, palmitoylation is reversible. Interestingly, it happens after translational modification, and it is a process that is able to alter the localization, stability, and function of hundreds of proteins in our cells. By attaching fatty acids to proteins, palmitoylation regulates the activation of ~2,000 human proteins (10% of the proteome), influencing various protein functions such as signaling, membrane trafficking, and subcellular localization.

Given the wide range of impact of palmitoylation on cellular events, the misregulation of palmitoylation plays a significant role in a variety of human pathologies. In particular, S-palmitoylation is essential for the function of many high-value drug targets, in addition to NRAS, such as STING, STAT3 and TEAD, which are often mutated and display altered expression patterns in various forms of cancer. Palmitoylation has also been linked to several diseases beyond cancer, including neurodegenerative diseases like Alzheimer's and Huntington's disease, which speaks to the broad potential of palmitoylation-targeted drugs. Palm Therapeutics leverages this biology to inhibit palmitoylation in specific targets, presenting a therapeutic strategy that holds immense promise for patients and as a drug development opportunity.

Underlying Palm Therapeutics’ discovery pipeline is the first screening platform that enables high-throughput discovery of selective palmitoylation inhibitors. Palm Therapeutics can screen large compound libraries and identify palmitoylation inhibitors that are selective to a specific target. This proprietary technology has allowed them to build a large data set of palmitoylation inhibitors and gain a unique, data-driven understanding of how to drug palmitoylation. Using their screening platform, Palm Therapeutics has identified multiple novel palmitoylation inhibitors that are specific to NRAS. They are now in the process of screening their hits for in-vitro efficacy and refining their selection to select a lead and further optimize through preclinical development. Palm Therapeutics' successful inhibition of NRAS could pave the way to developing novel therapeutics for over 2,000 other proteins that are also regulated by palmitoylation.

Supporting exciting science with Palm Therapeutics

Dr. Andrew Rudd’s career has centered around developing chemical tools to interrogate biological lipids and their roles in disease. He received his Ph.D. in chemistry from UC San Diego where he authored eight high-impact papers and was the recipient of several awards. During his PhD work, Dr. Rudd developed the first small molecule probes for directly inhibiting protein palmitoylation in cells. His work in academia has set the stage for the future by building a high-throughput platform capable of identifying and characterizing many more palmitoylation inhibitor molecules with therapeutic effects. Palm’s scientific co-founder, Professor Neal Devaraj has led pioneering research in the field of lipid chemistry at UC San Diego, Stanford and MIT, with research spanning artificial cells, lipid membranes, and bioconjugation.

Tachyon Ventures takes pride in embracing novel science early on, and we are thrilled to be investing in Palm Therapeutics to help champion innovation in palmitoylation-based therapies. As we move forward, we are excited about the many possibilities that lie ahead and the positive impact our collective efforts will have on patients affected by NRAS mutations to start.